P1465: SAFETY AND EFFICACY OF APOTRANSFERRIN INFUSION IN PATIENTS WITH BETA-THALASSEMIA INTERMEDIA, THE AIM STUDY
Authors: Kadère Konté, Dorine Swinkels, Ilona Kleine Budde, Erfan Nur, Bart Biemond
Journal: HemaSphere (2023)

Topic: 27. Thalassemias Background: Background Beta-thalassemia is characterized by ineffective erythropoiesis resulting in iron overload, leading to increased free circulating non-transferrin bound iron (NTBI). Induction of supernormal transferrin levels in a transgenic mouse model of beta-thalassemia intermedia, reduced haemolysis, normalized NTBI levels, improved red blood cell survival and splenomegaly. Aims: The aim of our study was to investigate the safety and efficacy of apotransferrin administration on markers of iron metabolism, erythropoiesis, and spleen size in patients with beta-thalassemia intermedia. Methods: This single-arm interventional trial was conducted in a tertiary teaching hospital in Amsterdam, The Netherlands. Sponsor: Prothya Biosolutions. Eligibility criteria were: adults with non-transfusion dependent beta-thalassemia intermedia (NTDTI) with haemoglobin (Hb) levels <10 g/dL or transfusion dependent beta-thalassemia intermedia (TDTI), adequate renal and hepatic function. Apotransferrin (Prothya Biosolutions B.V., The Netherlands) was given intravenously at a dose of 170mg/kg every 2 weeks following a loading dose of 170 mg/kg at day -1. Thereafter the dose was increased to 340 mg/kg every 14 days without a loading dose. Treatment duration was 14 weeks in NTDTI patients and 18 in TDTI patients. Response criteria were: >1.5 g/dL rise of Hb levels in NTDTI patients or >50% reduction of transfusion dependency in TDTI patients. Pharmacokinetics (PK) of apotransferrin were studied at week 4 or 6 by sampling at 5 min, 2 hours, 1, 4, 7 and 14 days following apotransferrin infusion. Iron, transferrin, transferrin saturation, NTBI, hepcidin and soluble transferrin receptor (sTfR) were determined. Spleen size was assessed by echocardiography in the 170mg/kg study group, by MRI in the 340mg/kg study group. Parametric data was described by mean and SD, non-parametric data by median and IQR (range if n < 4). Results: Patients with beta-thalassemia intermedia were included, 3 patients (2 NTDTI, 1 TDTI, median age 43 (range 26 – 60), 3 female) 170 mg/kg and 5 patients (3 NTDTI, 2 TDT, median age 44 (IQR 27 – 53), 3 female)), 340mg/kg, one patient appeared to have thalassemia trait. Two subjects were included in both groups. Hb levels in NTDTI patients and transfusion dependency in TDTI patients showed no increase. Transferrin levels peaked 5 minutes after infusion and returned to pre-dose level at day 14 (figure 1). Baseline-corrected t1/2term was 104.9 hours (SD ±4.37 days) in patients treated with 340 mg/kg, the uncorrected and baseline-corrected t1/2term for 170mg/kg could not be assessed due to a quick return to pre-dose. The average additional transferrin concentration on top of endogenous production in patients treated with 170mg/kg was 0.99 (± 0.117) and 2.7 g/L (± 0.945) with 340mg/kg. NTBI levels became undetectable (<0.47µM) 5 minutes after infusion, including 2 patients with already undetectable levels at baseline, and returned to baseline 24-168 hours after infusion (figure 1). Treatment with apotransferrin did not alter iron levels, transferrin saturation, hepcidin levels and STfR, no reduction in spleen size was observed. Administration of apotransferrin appeared to be safe. Most adverse events were mild, no serious adverse events occurred. Summary/Conclusion: Despite the rise in plasma transferrin levels resulting in a temporary reduction in NTBI levels after apotransferrin infusion, no effect on parameters of iron metabolism and erythropoiesis was observed in contrast to the observations in the mouse model. It remains to be established whether higher apotransferrin doses may result in improved erythropoiesis and reduced haemolysis in patients with beta-thalassemia intermedia.Keywords: beta thalassemia, Thalassemia